Our previous work under the RMRCE demonstrates that immunological protection against a Francisella tularensis infection can be elicited with an acellular vaccine, and in particular, a membrane preparation from this bacterium admixed with an adjuvant inducing a Th1 response is required to generate a protective adaptive immune response. Further, the level of protection elicited by a specific antigen preparation can be dramatically altered based on the adjuvant and route of delivery. Thus, tools are available to assess more precisely the innate and adaptive responses required for protection against F. tularensis. The humoral and cellular immune responses are both required to achieve optimal protection, with a B1b cell mediated IgM response being of greatest importance for early (3 days post-vaccination) protective immunity. These data along with the observation that the membrane protein fraction (MPF) admixed with the CLDC adjuvant stimulates inactivated macrophages to clear virulent F. tularensis leads us to hypothesize that surface structures of F. tularensis are critical targets for vaccine development and that stimulation of the proper innate response and T cell independent humoral immunity against surface structures can be exploited for a therapeutic vaccine to augment standard antibiotic treatment against F. tularensis and prevent relapse. To further these studies we will 1) identify F. tularensis surface proteins and non-protein structures that are targets for vaccine and therapeutic development; 2) elucidate protective immune responses elicited by adjuvant complexed accellular preparations and LVS vaccination; and 3) assess therapeutic vaccination to augment conventional chemotherapeutic treatment of tularemia and prevent relapse. This research project fits within the RMRCE Integrated Research Focus on Immunomodulation, Adjuvants and Vaccines, and will interact directly with RP1.2 and utilize the resources of Cores E and F.